This invention pertains to an osmotic device for the controlled delivery of a maximum amount of active agents to an environment of use. More particularly, it pertains to an osmotic device that increases in size during use thereby providing a relatively faster and more complete delivery of active agent.
Osmotic devices have demonstrated utility in delivering useful active agents such as medicines, nutrients, food products, pesticides, herbicides, germicides, algaecides, chemical reagents, and others known to those of ordinary skill to an environment of use in a controlled manner over prolonged periods of time. Known devices include tablets, pastilles, pills or capsules and others that use osmotic pressure to control the release of the active agent contained in the core of the osmotic device. Some osmotic devices may also include layers comprising one or more materials that are subject to erosion or that slowly dissolve in the environment of use thereby gradually dispensing the active agent. Known devices generally suffer from an inability to dispense all or substantially all the active agent from the core prior to the loss of osmotic pressure that occurs at osmotic equilibrium.
U.S. Pat. No. 4,088,864 to Theeuwes et al. (xe2x80x9cTheeuwes et al. ""864) discloses a high speed process for forming outlet passageways in the walls of osmotic devices for release of the contents of the osmotic device comprising: a) moving the pills in succession along a predetermined path at a predetermined velocity; b) tracking the moving pills seriatim at said velocity with a laser of a wavelength which is absorbable by said walls by oscillating the optical path of the laser back and forth over a predetermined section of the pill path at said velocity; c) firing the laser during said tracking; d) adjusting the laser beam dimension at said wall, the laser power and the firing duration such that the laser beam is capable of piercing the wall; and e) forming, with the laser beam, an outlet passageway 4 to 2000 microns in diameter in the wall. Theeuwes et al. ""864 does not disclose a process for forming a passageway that increases in size during use of the osmotic device.
Theeuwes et al. ""864 also discloses an apparatus for forming outlet passageways in the walls of osmotic devices for release of the contents of the osmotic device comprising: a) a support frame; b) a laser operating in a pulse mode; c) an optical pill tracking mechanism; d) a rotary pill indexer; and e) an electrical power supply to supply and control power for the laser, the tracking mechanism, and the indexer. Theeuwes et al. ""864 does not disclose an apparatus for forming a preformed passageway that increases in size during use of the osmotic device.
U.S. Pat. No. 4,014,334 to Theeuwes et al. (xe2x80x9cTheeuwes et al. ""334xe2x80x9d) discloses an osmotic device for the controlled and continuous delivery of a drug wherein the device comprises: a) a core containing a drug and an osmotic agent; b) a semipermeable laminate, surrounding the core, which includes an external semipermeable lamina and an internal semipermeable lamina; and c) a passageway which communicates the core with the exterior of the device. The two semipermeable laminae maintain their chemical and physical integrity in the presence of the drug and fluid from the environment. The passageway of Theeuwes et al. ""334 includes a passageway, orifice or bore through the laminate formed by mechanical procedures, or by eroding an erodible element, such as a gelatin plug, in the environment of use. Theeuwes et al. ""334 does not disclose a preformed passageway that increases in size during use of the osmotic device.
U.S. Pat. No. 4,576,604 to Guittard et al. (xe2x80x9cGuittard et al. ""604xe2x80x9d) corresponds to Argentina Patent No. 234,493 and discloses several different embodiments of an osmotic device having a drug in the core and at least one lamina surrounding the core. Specifically, one embodiment of the osmotic device comprises: a) a core containing a drug formulation which can include an osmotic agent for controlled release of the drug; b) a semipermeable wall comprising an inner semipermeable lamina, a middle microporous lamina, and an outer water soluble lamina containing drug; and c) a passageway which communicates the core with the exterior of the device. Guittard et al. ""604 does not disclose a preformed passageway that increases in size during use of the osmotic device.
U.S. Pat. No. 4,673,405 to Guittard et al (xe2x80x9cGuittard et al. ""405xe2x80x9d) discloses an osmotic device comprising: a) a core, or compartment, containing a beneficial agent; b) an inert semipermeable wall containing a beneficial agent surrounding the core; and c) at least one passageway in the wall of the osmotic device which is formed when the osmotic device is in the fluid environment of use and the fluid contacts and thus releases the beneficial agent in the wall, wherein the formed passageway communicates with the compartment in the osmotic device and the exterior of the device for dispersing the beneficial agent from the compartment when the device is in the fluid environment of use. Guittard et al. ""405 discloses the use of an erodible element to form the passageway; however, it does not disclose a preformed passageway that increases in size during use of the osmotic device.
U.S. Pat. No. 5,558,879 to Chen et al. (xe2x80x9cChen et al. ""879xe2x80x9d) discloses a controlled release tablet for water soluble drugs in which a passageway is formed in the environment of use, i.e., the GI tract of a person receiving the formulation. Specifically, the controlled release tablet consists essentially of: a) a core containing a drug, 5-20% by weight of a water soluble osmotic agent, a water soluble polymer binder and a pharmaceutical carrier; and b) a dual layer membrane coating around the core consisting essentially of: (1) an inner sustained release coating containing a plasticized water insoluble polymer and a water soluble polymer; and (2) an outer immediate release coating containing a drug and a water soluble polymer. Although Chen et al ""879 discloses the formation of a passageway in a controlled release tablet in an environment of use to form an osmotic tablet, the passageway is not a preformed passageway that increases in size during use of the osmotic device.
U.S. Pat. No. 4,810,502 to Ayer et al. (xe2x80x9cAyer et al. ""502xe2x80x9d) discloses an osmotic dosage form for delivering pseudoephedrine (Ps) and brompheniramine (Br) which comprises: a) a core containing Ps and Br; b) a wall surrounding the core comprising cellulose acylate and hydroxypropylcellulose; c) a passageway in the wall for delivering the drug; and d) a lamina on the outside of the wall comprising Ps, Br, at least one of hydroxypropylcellulose and hydroxypropyl methylcellulose, and poly(ethylene oxide) for enhancing the mechanical integrity and pharmacokinetics of the wall. Ayer et al. ""502 does not disclose a preformed passageway that increases in size during use of the osmotic device.
U.S. Pat. No. 4,801,461 to Hamel et al. (xe2x80x9cHamel et al ""461xe2x80x9d) discloses an osmotic dosage form for delivering pseudoephedrine (Ps). Specifically, the osmotic dosage form comprises: a) a core containing varying amounts of Ps; b) a semipermeable wall surrounding the core comprising varying amounts of cellulose acetate or cellulose triacetate and varying amounts of hydroxypropylcellulose; c) a passageway in the wall for delivering the drug from the core; and optionally d) a lamina on the outside of the wall comprising Ps. The core can also contain one or more of sodium chloride, microcrystalline cellulose, hydroxypropyl methylcellulose, magnesium stearate, and poly(vinylpyrrolidone). The passageway of this device can extend through the semipermeable wall alone or through both the semipermeable wall and the outer lamina. The passageway also includes materials that erode or leach in the environment of use. A variety of erodible materials are listed as suitable for use in forming the passageway. Hamel et al. ""461 does not, however, disclose a preformed passageway that increases in size during use of the osmotic device.
U.S. Pat. No. 5,681,584 to Savastano et al. (xe2x80x9cSavastano et al. ""584xe2x80x9d) discloses a controlled release drug delivery device comprising: a) a core containing a drug, an optional osmotic agent and optional excipients; b) a delayed release jacket comprising at least one of a binder, an osmotic agent and a lubricant surrounding the core; c) a semipermeable membrane surrounding the delayed release jacket and optionally having a passageway; d) a drug-containing layer either on the outside of the semipermeable membrane or between the semipermeable membrane and the delayed release jacket; and e) an optional enteric coat either on the outside of the drug-containing layer, between the drug-containing layer and the semipermeable membrane or on the outside of the semipermeable membrane when the drug-containing layer is between the delayed release jacket and the semipermeable membrane. Thus, the device of Savastano et al. ""584 does not provide for release of active agent via a preformed passageway that increases in size during use of the osmotic device.
U.S. Pat. No. 6,004,582 to Faour et al. (Faour et al. ""582) discloses a multi-layered osmotic device comprising a core surrounded by a semipermeable membrane having a preformed hole in it. The hole is subsequently plugged by an inert erodible water soluble coating and then covered with a water soluble drug-containing coating. This patent does not disclose an osmotic device having a preformed passageway that increase in size during use.
U.S. Pat. No. 5,873,793 to Emerton et al. (Emerton et al. ""793) and U.S. Pat. No. 5,376,771 to Roy (Roy ""771) disclose laser apparatuses capable of simultaneously forming a plurality of holes on the semipermeable membrane of an osmotic device. These patents do not disclose an osmotic device having a preformed passageway that increase in size during use.
Additional exemplary osmotic devices for the controlled delivery of active agents are described in U.S. Pat. No. 3,845,770 and Argentina Patent No. 199,301 which disclose an osmotic device formed by a wall that surrounds a compartment-housing agent. The wall has a passageway or orifice that links the compartment to the environment of use. The wall is made of semipermeable material that is semipermeable to an external fluid and impermeable to an active agent within the device. Neither of these patents discloses a preformed passageway that increases in size during use of the osmotic device.
While the prior art discloses a wide variety of release mechanisms used in osmotic devices, no single release mechanism provides a passageway designed to increase in size during use so that controlled delivery of all or substantially all the amount of active agent is provided or so that the rate of release of the drug increases over time. A method of making such an osmotic device has now been discovered. The present osmotic device overcomes many of the disadvantages inherent in related prior art osmotic devices because it is capable of providing approximately complete delivery of the active substance contained in the core and an increased release rate of active substance during use, and it enables release of large particle size and/or generally insoluble active agents.
Almost invariably for prior art devices, not all active agent is released before osmotic equilibrium is reached. The present invention, however, overcomes this disadvantage by providing an osmotic device having a preformed passageway that increases in size during use, thereby allowing controlled delivery to an environment of use of an active substance contained in the core of the osmotic device. The present invention also provides a method for making an osmotic device having a preformed passageway that increases in size during use. The benefits provided by the present invention include: 1) approximately complete delivery of the active substance contained in the core; 2) an increased release rate of active substance during use as the increase in size of the passageway permits more of the contents of the core to be released more quickly through the larger passageway; and 3) enablement of the release of large particle size and/or generally insoluble active agents.
One aspect of the present invention provides an osmotic device for the controlled delivery of approximately all of an active substance contained in the core of the osmotic device, wherein the osmotic device comprises: a) a core comprising an active agent, such as nifedipine, at least one osmopolymer, and at least one excipient; b) a semipermeable membrane surrounding the core; c) a preformed passageway in the semipermeable membrane for release of the contents of the core where the passageway increases in size during use of the osmotic device; wherein the passageway provides an increased release rate of active agent during use as compared to an osmotic device not having such a passageway; and the passageway permits release of approximately all of the contents of the core.
Specific embodiments of the invention include those embodiments wherein: a) at least 80% of the active agent is released by the end of use; b) at least 90% of the active agent is released by the end of use; c) the preformed passageway increases in size from its initial size by at least 10%; d) the preformed passageway increases in size from its initial size by at least 25%; e) the preformed passageway increases in size from its initial size by at least 50%; f) the preformed passageway increases in size from its initial size by at least 75%; g) the preformed passageway increases in size from its initial size by at least 100%; h) the preformed passageway increases in size because of mechanical means used during manufacture; i) the preformed passageway expands in size by dissolution or breakage of the semipermeable membrane; j) the preformed passageway expands in size in a predetermined manner; k) the core contains a swellable material; l) the core comprises a nucleus that is coated with active agent and at least one excipient; m) the exterior of the semipermeable membrane has at least one coating that effects the operation of the osmotic device in a manner according to the properties of the coating; and/or n) the preformed passageway increases in size due to an increase in the viscosity, molecular weight, or degree of substitution of the at least one excipient in the core.
One aspect of the present invention provides a method of preparing the osmotic device, wherein a core comprising an active agent and at least one excipient is covered with a semipermeable membrane that is perforated to form at least one preformed passageway that increases in size during use of the osmotic device. In this aspect, the invention provides a method of preparing an osmotic device having a preformed passageway that increases in size during use, wherein the method comprises the steps of: a) forming a core comprising an active agent, such as nifedipine; b) covering the core with a semipermeable membrane; c) perforating the semipermeable membrane with a laser to form a preformed passageway, wherein the laser generally delivers a laser beam of sequential pulses having a predetermined pulse period of greater duration than a pulse period used to make similar osmotic devices that do not have passageways that increase in size; and the laser beam is generally adjusted to fire with a predetermined pulse width of lesser duration than a pulse width used to make similar osmotic devices that do not have passageways that increase in size.
Other aspects of the invention provide a method of making the osmotic device wherein the preformed passageway is formed by other mechanical means; by variations in the viscosity, the molecular weight, or the degree of substitution of the at least one excipient; by the use of plasticizers in the semipermeable membrane; or by the use of a brittling agent.
The present invention further provides a method for using the osmotic device having a passageway that increases in size during use, wherein the osmotic device is generally used in a manner to provide a therapeutic effect on a human.
The at least one excipient is independently selected at each occurrence from the group consisting of an osmagent, an osmopolymer, a lubricant, a glidant, adsorbent, antioxidant, buffering agent, colorant, flavorant, sweetening agent, tablet antiadherent, binder, tablet and capsule diluent, tablet direct compression excipient, tablet disintegrant, tablet or capsule opaquant and/or tablet polishing agent.
The preformed passageway increases in size in a predetermined manner or in a random manner, depending on the method used to form the passageway. The size of the preformed passageway increases from its initial size over time, up to a size as determined by the method and materials used to form the osmotic device. The passageway does not generally decrease in size after all or approximately all of the contents of the core have been released.
The active agents can include compounds such as biologically or pharmacologically active agents, medicines, nutrients, food products, insecticides, pesticides, herbicides, germicides, algaecides, fungicides, chemical reagents, growth regulating substances, parasiticides, sex sterilants, fertility promoters, biocides, rodenticides, disinfectants, anti-oxidants, plant growth promoters, preservatives, fermentation agents, fertility inhibitors, air purifiers, micro-organism attenuators, catalysts, foods, food supplements, nutrients, cosmetics, vitamins, and other agents that benefit the environment of use.
Different environments for use of the osmotic device include biological environments such as the oral, ocular, nasal, vaginal, glands, gastrointestinal tract, rectum, cervical, intrauterine, arterial, venous, otic, sublingual, dermal, epidermal, subdermal, implant, buccal, bioadhesive, mucosal and other similar environments. Likewise, it may be used in aquariums, industrial warehouses, laboratory facilities, hospitals, chemical reactions and other facilities.
Other features, advantages and embodiments of the invention will become apparent to those skilled in the art by the following description, accompanying examples and appended claims.
The following drawings are part of the present specification and are included to further demonstrate certain aspects of the invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of the specific embodiments presented herein.
FIG. 1 depicts a release profile of an exemplary formulation of the osmotic device, formed in accordance with Example 1.
FIG. 2 depicts a drug release profile as provided by a commercial product.
FIG. 3 depicts a plasma profile of an exemplary formulation of the osmotic device prepared according to Example 1.
FIG. 4 depicts a sectional side view of an exemplary embodiment of an osmotic device having a passageway that increases in size during use.
FIG. 5 depicts a top view of the device of FIG. 4.
FIG. 6 depicts a sectional side view of an alternative embodiment of an osmotic device having a passageway that increases in size during use, wherein a plug blocks the passageway.
FIG. 7 depicts various alternate embodiments for an aperture according to the invention.
FIG. 8 depicts a top plan view of an exemplary preformed passageway after it has increased size.